Transcript S-adenosylmethionine

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S-adenosylmethionine
• Important methyl-donating coenzyme
– Can also donate methylene groups, amino groups, ribosyl groups and
aminopropyl groups
– Reactivity based on electrophilic nature of atoms surrounding S+
– Tetrahydrofolate is another important methyl carrier
• Also important in initiating reractions by extracting H (i.e. H∙) via
5’deoxyadenosyl radical
– Important but not well understood class of enzymes – “Radical SAM”
enzymes
– These reactions remind me very much of Vitamin B12-dependent reactions
(which are usually rearrangements)
– Include ribonucleotide reductase
– Bioinformatics (based in part on C-X-X-X-C-X-X-C motif of unusual 3 Cysliganded 4Fe4S center) indicates there are liekly hundreds of these proteins
• Low levels of folate can result in low levels of SAM (or SAMe) since
folate is required for homocysteine  methionine
• Not found in dietary sources (due to instability, I’m pretty sure?), easily
synthesized in us (when healthy)
NH2
SAM or SAMe
N
N
CH
HC
N
N
-O C
2
CH3
H2C
S+
CH2
CH2
CH
O
HC
NH3+
CH
HC
CH
OH HO
NH2
SAH
N
N
-O C
2
CH
HC
N
N
H2C
S
CH2
CH2
CH
O
HC
CH
HC
CH
OH HO
NH3+
• Clinical uses have included:
– Antidepressant (mechanism unknown)
– Treatment of neurological disorders (“ “)
– Antiosteoarthritis (“ “)
– Fibromyalgia (“ “)
– Treatment of liver disease
• Liver disease results in increase in blood
methionine, less SAMe (etiology unknown), low
levels of glutathione
• MAT enzyme seems to be involved (methionine
adenosyl transferase, see overview)
• Parenteral and oral SAMe administration results in
increased glutathione levels (and decreased
methionine levels (?)
The main parts of the “SAMe cycle”
Folate-dependent
Vitamin B12
• R = -CH3 (methylcobalamin) –CN (cyanocobalamin,
stable vitamin form), -Ad (adenosylcobalamin, active
coenzyme)
• Catalyzes rearrangements
• One example: methylmalonyl CoA mutase, which is
important in breakdown of isoleucine, methionine,
threonine, and valine as well as odd-chain fatty acids
and cholesterol
H2C
=
R
CH2
R
CoIII
R
CH
CoIII
R
H3C
+
+
H2C
Ad
Ad
Ad
H2C
CoII
Ad
H3C
CoII
Ad
R
H
C
CoIII
R